Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A
H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial.
Author(s): Kreijtz JH(1), Goeijenbier M(1), Moesker FM(1), van den Dries L(1), Goeijenbier
S(1), De Gruyter HL(1), Lehmann MH(2), Mutsert Gd(1), van de Vijver DA(1), Volz
A(2), Fouchier RA(1), van Gorp EC(1), Rimmelzwaan GF(1), Sutter G(2), Osterhaus
AD(3).
Affiliation(s): Author information:
(1)Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands. (2)Institute
for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich,
Munich, Germany; German Centre for Infection Research, Munich, Germany.
(3)Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands; Artemis,
Utrecht, Netherlands; Center for Infection Medicine and Zoonoses Research,
University of Veterinary Medicine, Hannover, Germany. Electronic address:
a.osterhaus@erasmusmc.nl.
Publication date & source: 2014, Lancet Infect Dis. , 14(12):1196-207
BACKGROUND: Modified vaccinia virus Ankara (MVA) is a promising viral vector
platform for the development of an H5N1 influenza vaccine. Preclinical assessment
of MVA-based H5N1 vaccines showed their immunogenicity and safety in different
animal models. We aimed to assess the safety and immunogenicity of the
MVA-haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals.
METHODS: In a single-centre, double-blind phase 1/2a study, young volunteers
(aged 18-28 years) were randomly assigned with a computer-generated list in equal
numbers to one of eight groups and were given one injection or two injections
intramuscularly at an interval of 4 weeks of a standard dose (10(8) plaque
forming units [pfu]) or a ten times lower dose (10(7) pfu) of the MVA-H5-sfMR
(vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus
[H5N1 subtype]) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians
who examined and administered the vaccine were masked to vaccine assignment.
Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster
immunisation 1 year after the first immunisation. Primary endpoint was safety.
Secondary outcome was immunogenicity. The trial is registered with the Dutch
Trial Register, number NTR3401.
FINDINGS: 79 of 80 individuals who were enrolled completed the study. No serious
adverse events were identified. 11 individuals reported severe headache and
lightheadedness, erythema nodosum, respiratory illness (accompanied by
influenza-like symptoms), sore throat, or injection-site reaction. Most of the
volunteers had one or more local (itch, pain, redness, and swelling) and systemic
reactions (rise in body temperature, headache, myalgia, arthralgia, chills,
malaise, and fatigue) after the first, second, and booster immunisations.
Individuals who received the 10(7) dose had fewer systemic reactions. The
MVA-H5-sfMR vaccine at 10(8) pfu induced significantly higher antibody responses
after one and two immunisations than did 10(7) pfu when assessed with
haemagglutination inhibition geometric mean titre at 8 weeks against H5N1
A/Vietnam/1194/2004 (30·2 [SD 3·8] vs 9·2 [2·3] and 108·1 [2·4] vs 15·8 [3·2]).
27 of 39 eligible individuals were enrolled in the booster immunisation study. A
single shot of MVA-H5-sfMR 10(8) pfu prime immunisation resulted in higher
antibody responses after the booster immunisation than did two shots of
MVA-H5-sfMR at the ten times lower dose.
INTERPRETATION: The MVA-based H5N1 vaccine was well tolerated and immunogenic and
therefore the vaccine candidates arising from the MVA platform hold great promise
for rapid development in response to a future influenza pandemic threat. However,
the immunogenicity of this vaccine needs to be compared with conventional H5N1
inactivated non-adjuvanted vaccine candidates in head-to-head clinical trials.
FUNDING: European Research Council.
|